CLINICAL REVIEW DIVISION OF GASTROENTEROLOGY PRODUCTS Application Type NDA Submission Number 22-101/000 Letter Date Sept. 27, 2006 Stamp Date Sept. 29, 2006 PDUFA Goal Date July 29, 2007 Reviewer Name Wen-Yi Gao, M.D., Ph.D. Review Completion Date July 19, 2007 Established Name Esomeprazole magnesium (Proposed) Trade Name Nexium Therapeutic Class Proton Pump Inhibitor Applicant AstraZeneca Priority Designation S Formulation Delayed-Release Granules for Oral Suspension Dosing Regimen 10 mg once daily for up to 8 weeks Indication Short-term treatment of symptomatic GERD and erosive esophagitis Intended Population 1 to 11 years of age Clinical Review Wen-Yi Gao, M.D., Ph.D. NDA 22-101/000 Nexium (esomeprazole) Table of Contents CLINICAL REVIEW..................................................................................................................................................1 1 EXECUTIVE SUMMARY................................................................................................................................5 1.1 RECOMMENDATION ON REGULATORY ACTION ...........................................................................................5 1.2 RECOMMENDATION ON POSTMARKETING ACTIONS ....................................................................................5 1.2.1 Risk Management Activity ....................................................................................................................5 1.3 SUMMARY OF CLINICAL FINDINGS ..............................................................................................................6 1.3.1 Brief Overview of Clinical Program......................................................................................................6 1.3.2 Efficacy..................................................................................................................................................6 1.3.3 Safety.....................................................................................................................................................7 1.3.4 Dosing Regimen and Administration.....................................................................................................8 1.3.5 Drug-Drug Interactions..........................................................................................................................9 1.3.6 Special Populations................................................................................................................................9 2 INTRODUCTION AND BACKGROUND ....................................................................................................10 2.1 PRODUCT INFORMATION ...........................................................................................................................10 2.2 CURRENTLY AVAILABLE TREATMENT FOR INDICATIONS..........................................................................10 2.3 AVAILABILITY OF PROPOSED ACTIVE INGREDIENT IN THE UNITED STATES ..............................................10 2.4 IMPORTANT ISSUES WITH PHARMACOLOGICALLY RELATED PRODUCTS...................................................10 2.5 PRESUBMISSION REGULATORY ACTIVITY .................................................................................................10 2.6 OTHER RELEVANT BACKGROUND INFORMATION......................................................................................12 3 SIGNIFICANT FINDINGS FROM OTHER REVIEW DISCIPLINES ....................................................12 3.1 CMC (AND PRODUCT MICROBIOLOGY, IF APPLICABLE) ...........................................................................12 3.2 ANIMAL PHARMACOLOGY/TOXICOLOGY ..................................................................................................13 2 Clinical Review Wen-Yi Gao, M.D., Ph.D. NDA 22-101/000 Nexium (esomeprazole) 4 DATA SOURCES, REVIEW STRATEGY, AND DATA INTEGRITY.....................................................13 4.1 SOURCES OF CLINICAL DATA ....................................................................................................................13 4.2 TABLES OF CLINICAL STUDIES ..................................................................................................................14 4.3 REVIEW STRATEGY ...................................................................................................................................14 4.4 DATA QUALITY AND INTEGRITY ...............................................................................................................15 4.5 COMPLIANCE WITH GOOD CLINICAL PRACTICES.......................................................................................15 4.6 FINANCIAL DISCLOSURES..........................................................................................................................15 5 CLINICAL PHARMACOLOGY ...................................................................................................................15 5.1 PHARMACOKINETICS .................................................................................................................................15 6 INTEGRATED REVIEW OF EFFICACY ...................................................................................................17 6.1 INDICATION ...............................................................................................................................................17 6.1.1 Methods ...............................................................................................................................................17 6.1.2 General Discussion of Endpoints.........................................................................................................17 6.1.3 Study Design........................................................................................................................................18 6.1.4 Efficacy Findings.................................................................................................................................20 6.1.5 Clinical Microbiology..........................................................................................................................31 6.1.6 Efficacy Conclusions ...........................................................................................................................31 7 INTEGRATED REVIEW OF SAFETY ........................................................................................................32 7.1 METHODS AND FINDINGS ..........................................................................................................................32 7.1.1 Deaths ..................................................................................................................................................33 7.1.2 Other Serious Adverse Events .............................................................................................................33 7.1.3 Dropouts and Other Significant Adverse Events .................................................................................34 7.1.4 Other Search Strategies........................................................................................................................35 7.1.5 Common Adverse Events ....................................................................................................................35 3 Clinical Review Wen-Yi Gao, M.D., Ph.D. NDA 22-101/000 Nexium (esomeprazole) 7.1.7 Laboratory Findings.............................................................................................................................36 7.1.8 Vital Signs ...........................................................................................................................................36 7.1.9 Electrocardiograms (ECGs).................................................................................................................37 7.2 ADEQUACY OF PATIENT EXPOSURE AND SAFETY ASSESSMENTS ..............................................................37 7.2.1 Description of Primary Clinical Data Sources (Populations Exposed and Extent of Exposure) Used to Evaluate Safety ..................................................................................................................................................37 7.2.3 Adequacy of Overall Clinical Experience ...........................................................................................39 7.2.8 Assessment of Quality and Completeness of Data ..............................................................................39 7.3 SUMMARY OF SELECTED DRUG-RELATED ADVERSE EVENTS, IMPORTANT LIMITATIONS OF DATA, AND CONCLUSIONS .........................................................................................................................................................39 8 ADDITIONAL CLINICAL ISSUES ..............................................................................................................39 8.1 DOSING REGIMEN AND ADMINISTRATION .................................................................................................39 8.2 DRUG-DRUG INTERACTIONS .....................................................................................................................40 8.3 SPECIAL POPULATIONS..............................................................................................................................40 8.4 PEDIATRICS ...............................................................................................................................................40